期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 145, 期 46, 页码 25283-25292出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.3c08852
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DNA-encoded chemical library (DEL) is a widely used method for lead compound discovery. This study focuses on the design and utility of tyrosine-targeting DELs and successfully identifies tyrosine-targetable proteins as models for covalent inhibitors. The strategy of combining activity-based proteome profiling and covalent DEL enrichment shows the potential use of this methodology in further covalent drug discovery.
DNA-encoded chemical library (DEL) has been extensively used for lead compound discovery for decades in academia and industry. Incorporating an electrophile warhead into DNA-encoded compounds recently permitted the discovery of covalent ligands that selectively react with a particular cysteine residue. However, noncysteine residues remain underexplored as modification sites of covalent DELs. Herein, we report the design and utility of tyrosine-targeting DELs of 67 million compounds. Proteome-wide reactivity analysis of tyrosine-reactive sulfonyl fluoride (SF) covalent probes suggested three enzymes (phosphoglycerate mutase 1, glutathione s-transferase 1, and dipeptidyl peptidase 3) as models of tyrosine-targetable proteins. Enrichment with SF-functionalized DELs led to the identification of a series of tyrosine-targeting covalent inhibitors of the model enzymes. In-depth mechanistic investigation revealed their novel modes of action and reactive ligand-accessible hotspots of the enzymes. Our strategy of combining activity-based proteome profiling and covalent DEL enrichment (ABPP-CoDEL), which generated selective covalent binders against a variety of target proteins, illustrates the potential use of this methodology in further covalent drug discovery.
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